Huntington's disease (HD) is a neurodegenerative disorder typically diagnosed in mid-life that is caused by expansion of an otherwise polymorphic CAG trinucleotide repeat, leading to a lengthened polyglutamine tract in the amino terminal region of the large (>350 kD) huntingtin protein. Strong evidence from human studies and mouse model studies indicate that HD is a lifelong disorder. The mutation causes a gain-of- function of the huntingtin protein to trigger a pathogenic process that produces detectable phenotypic differences many years before the traditional diagnosis, which is based upon characteristic motor symptoms. The prediagnosis phase of pathogenesis is now the subject of intense scrutiny by an NINDS-funded longitudinal study, PREDICT-HD, in which undiagnosed gene carriers are followed longitudinally and subjected to detailed phenotyping. This powerful approach, which offers the potential for moving the focus of therapeutic development to the decades prior to neurological disease diagnosis, is enabled by the fact that all individuals with HD have the same type of mutation, which can be determined at any time in life by a single PCR assay. That the disease is modifiable during this pre-diagnosis phase has been established by human genotype- phenotype studies, enabled by the fact that the precise length of the unique HD CAG expansion differs between individuals. There is a strong negative correlation between the number of CAG repeats and the age at onset of diagnostic neurological abnormalities in HD, such that the CAG repeat accounts for ~50% of the variation in age at diagnosis. Analysis of the remaining variance not explained by the length of the CAG repeat has shown that it is highly heritable, being due to genetic variation, elsewhere in the genome. The existence of these genetic modifiers indicates that it is possible to alter the course of HD. Identification of these modifier genes is therefore a top priority for HD research (and an example of an approach that can be applied in other late-onset genetic disorders), as it could provide clues to developing rational treatments that delay or prevent the pathogenic process from causing the ravages of the disease that ensue in the ~15 years of inexorable decline to ultimate death that now follows clinical diagnosis. We propose to identify genetic modifiers of HD pathogenesis by using genomewide association techniques in diagnosed HD individuals to identify genetic factors associated with the residual variance in age at diagnostic neurologic onset not explained by the CAG repeat, and to extend these analyses to pre-diagnosis phenotypes defined in the PREDICT-HD study. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a neurodegenerative disorder typically diagnosed in mid-life that is caused by the same type of mutation in all affected individuals, making it possible to identify those will suffer its ravages years before they can be diagnosed clinically. Genetic studies have showed that the human genome contains modifier genes that can hasten or delay the course of the disease. Identification of these genetic modifiers by the studies proposed here would provide new targets for therapeutic development that are already validated to work in human beings and would move the focus of treatment to the prevention or slowing of the disease process before the full damage has been done, in addition to traditional efforts to treat those already showing clinical symptoms. As such, the study will also act as a model for similar efforts in other disorders to target treatment prior to clinical disease onset. The preliminary written comments of the reviewers are reproduced below. These comments were prepared prior to the meeting and may not have been edited after the full committee discussion of your application.